Method for preparing biomedical surfaces

ABSTRACT

A method for selectively dissolving the beta (β) phase of a titanium alloy out of the surface of the alloy, thereby leaving behind a nano-scale porous surface having enhanced bonding properties with either a biological tissue, such as bone, or an adhesive material, such as a polymer or ceramic by immersing the alloy in an ionic aqueous solution containing high levels of hydrogen peroxide and then exposing the alloy to an electrochemical voltage process resulting in the selective dissolution of the beta phase to form a nano-topographic metallic surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/766,781, filed Feb. 10, 2006.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to biomedical surfaces and, morespecifically, to a method of preparing biomedical surfaces for enhancedbiological interaction and adhesion with adjoining materials or tissue.

2. Description of the Related Art

Porous surfaces have been used for over two decades to provide placesfor biological fixation between implant and tissue to take place.Typically these porous surfaces are processed by sintering, diffusionbonding, plasma spraying or other mechanism and create rough bead-likeor fiber-like surfaces. The spaces between these materials then serve assites where bone or other tissue can in-grow and attach to the implant.This process is called biological fixation and is used extensively inimplants (e.g., dental, hips and knees) to fix the device directly intothe bony substrate.

Nano-scale surface topography of implants has gained in interest inrecent years as it is becoming known that nano-topography of surfacescan have a significant effect on cell behavior on suchnano-topographically modified surfaces. Conventional nano-scaletopography formation is directed toward forming nanotubes or nanocolumnsusing etching/electrochemical processing. Other processes involve makingelectropolished surfaces. These techniques are frequently very expensiveto implement and are of reduced value in surfaces having recessedcavities. As a result, bone attachment is not always successful.

BRIEF SUMMARY OF THE INVENTION

It is a principal object and advantage of the present invention toprovide a method for forming biomedical surfaces having nanoscaletopography that is electrochemical.

It is an additional object and advantage of the present invention toprovide a method for forming biomedical surfaces having nanoscaletopography that provides faster, stronger and more robust interfacialadhesion to biological systems.

It is a further object and advantage of the present invention to providea method for forming biomedical surfaces having nanoscale topographythat is less costly.

It is a further object and advantage of the present invention to providea method for forming biomedical surfaces having nanoscale topographythat is applicable for use in connection with recessed cavities.

Other objects and advantages of the present invention will in part beobvious, and in part appear hereinafter.

In accordance with the foregoing objects and advantages, the presentinvention comprises a process for selectively dissolving one phase of atitanium alloy (the beta (β) phase of Ti-6Al-4V) out of the surface ofthe alloy, thereby leaving behind a nano-scale porous surface havingenhanced bonding properties with either a biological tissue, such asbone, or an adhesive material, such as a polymer or ceramic. The alloyis immersed into an ionic aqueous solution containing high levels ofhydrogen peroxide and then exposed to an electrochemical voltage processresulting in the selective dissolution of the beta phase. With specificvoltage conditions and ranges of hydrogen peroxide concentrationssurfaces of two phase titanium alloys made from Ti-6Al-4V can be inducedto selectively dissolve one phase, thereby forming a nanotopographicmetallic surface.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more fully understood and appreciated byreading the following Detailed Description in conjunction with theaccompanying drawings, in which:

FIG. 1 is a flowchart of a process according to the present invention.

FIGS. 2( a)-(b) are Scanning Electron Micrographs of Ti-6Al-4V: (a) at7000× after treatment with hydrogen peroxide and electrochemicaltreatment showing selective dissolution of the beta phase; and (b) at3500× after standard etching treatments with the beta phase stillintact.

FIG. 3 is a graph of potentiodynamic polarization plots of Ti-6Al-4V inhydrogen peroxide containing solutions.

FIG. 4 is a reproduction of an Atomic Force Microscopy image (height) ofTi-6Al-4V after selective dissolution of beta crystals (dark regions ofimage).

FIG. 5 is a SEM micrograph of Ti-6Al-4V after selective dissolution ofbeta phase.

FIGS. 6( a)-(c) are SEM micrographs of Ti-6Al-4V after processing asdescribed in Example 2: (a) holding for 1000 s at −0.5 V; (b) Holdingfor 1000 s at −0.1 V; and (c) holding for 1000 s at 0.1 V.

FIG. 7 is a SEM micrograph of Cp-Ti after processing in 1 M H₂O₂ PBSsolution.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to the drawings, wherein like reference numerals refer tolike parts throughout, the present invention comprises a method ofpreparing metallic biomedical surfaces for enhanced biologicalinteraction and/or enhanced adhesion with an adjoining material ortissue. The process involves a combination of a chemical andelectrochemical interaction between a multiphase titanium alloy, e.g.,Ti-6Al-4V, a two phase alloy system used in medical devices (ASTMF-136), and an electrochemical solution, e.g., a 0.154 M solution ofphosphate buffered saline modified by the addition of hydrogen peroxidein a molar concentration range of 0.3 to 5.0 M (or broader). Theelectrochemical solution in conjunction with a specific voltage processcauses the surface of the alloy to undergo selective dissolution of oneof the two phases of the alloy, thereby leaving a nanotopographicsurface roughness and modified oxide film character that providesenhanced ability of the metal surface to interact with adjacent tissuesor materials. Single phase titanium alloys (commercially pure titanium,grade 2, ASTM F-67 “Standard Specification for Unalloyed Titanium forSurgical Implant Applications”) may also have nanotopographic changesthat result from similar processes where the resulting surface appearspitted. The method of the present invention may also create a bioactivegel-likeoxide coating seen in non-electrochemically-driven surfacemodifications.

Referring to FIG. 1, in a process 10 according to the present inventionfor preparing nanotopographical surfaces, the alloy selected forpreparation may optionally be treated to prepare or alter its surfacemorphology 12. For example, the alloy may be mechanically polished withemory paper and/or Al₂O₃ particles suspended in water to yield a flatpolished surface. Alternatively, the alloy may be heated into itsbeta-phase region (e.g., above about 920° C.) to transforms themicrostructure when cooled back to room temperature into a Widmanstattenstructure that generally comprises needles/plates of alpha phase encasedin beta phase, and thus provides a surface morphology having fingers ofalpha with grooves around them.

Process 10 next involves immersing the alloy into an ionic aqueoussolution containing high levels of hydrogen peroxide 14, and thenexposing the surface to an electrochemical voltage process 16 resultingin the selective dissolution of the beta phase. Surfaces of titaniumalloys are covered with nanometer scale metal oxide films (known aspassive oxide films or conversion coatings) that result from thereaction of the surface metal with oxygen. These oxide films serve astenacious barrier coatings that limit subsequent electrochemical(corrosion) reactions and provide the high corrosion resistance of thesealloys. The oxide films on titanium alloys result in titanium alloysbeing known as the most biocompatible metals in use in medical devicestoday. When these surfaces are exposed to most aqueous electrolytesolutions, they remain in a passive state and will not allow enhancedcorrosion reactions to take place. Also, when titanium is exposed tohigh concentrations of hydrogen peroxide (with no external applicationof voltage), the effects of selective dissolution do not take place.However, with specific voltage conditions and ranges of hydrogenperoxide concentrations, the surfaces of two phase titanium alloys (madefrom Ti-6Al-4V) can be induced to selectively dissolve one phase.

To induce the selective dissolution effect, electrochemical voltageprocess 16 comprises a two-stage process of cathodically biasing 18 thesurface of the alloy relative to its open circuit potential to a morenegative voltage state (e.g., −1V vs Ag/AgCl reference electrode), andthen anodically raising the surface 20 of the alloy to within a range ofpotentials to induce the selective dissolution effect. The Ti-6Al-4Valloy may be cathodically biased to −1V Ag/AgCl for a period of severalminutes. The surface of the alloy is then brought up to a more anodicpotential (e.g., 0V Ag/AgCl) and allowed to sit at this potential for aperiod of time. If the electrochemical history is not applied and just apositive potential is applied, then selective dissolution effect willnot occur. Afterward, the surfaces may be cleaned, dried and imaged in ascanning electron microscope to determine the effect of process 10 onthe nanotopography of the alloy.

Hydrogen peroxide in an aqueous phosphate buffered saline solution ispreferably used as the ionic aqueous electrolyte solution to selectivelydissolve the beta phase of Ti-6Al-4V. There is a range of hydrogenperoxide concentrations that will result in this process and below whichit will not occur. A solution of hydrogen peroxide of 0.3 to 1M isneeded to induce the selective dissolution effect, but it may also occur(at different rates) with solution ranges outside the 0.3 M to 1M range.Although it is not clear what precise lower limit concentration caninduce this effect, the alloy will not selectively dissolve in theabsence of hydrogen peroxide.

FIG. 2 a shows an example of an alloy prepared in this manner. Theresultant surface shows that the beta grains of the Ti-6Al-4V alloy havebeen selective dissolved, thereby leaving behind small (micron-size andsmaller) surface pits into which biological tissue (e.g., bone cells,etc.) can grow and attach. It is likely that the process dissolves boththe alpha and the beta phases, however, it appears that the beta phaseis preferentially dissolved at a higher rate.

FIG. 2 b is of the same alloy after exposure to a standard etchingsolution (Kroll's Reagent) to reveal the typical microstructure of bothalpha and beta phases. One can compare the results from both treatmentsto see where the selective dissolution has occurred.

FIG. 3 shows polarization curves for Ti-6Al-4V in H₂O₂ containingsolutions where the alloy is first cathodically biased to −1V and thenpoteniodynamically scanned anodically. In performing the cathodic bias,the surface becomes much more active (with higher reduction currentsobserved compared to non-cathodically biased samples). When thesesurfaces are brought into the active region for corrosion, then theselective dissolution process can take place. It appears that hydrogenperoxide concentrations that will do this well are in the 1 M range.Note that when the surface is not first cathodically biased (the bluediamonds curve), the current density remains relatively low indicatingthat the surface oxide is still intact over the entire surface. However,the other surfaces were cathodically biased to −1V for a period of timeand then scanned anodically. The corrosion currents are one to twoorders of magnitude higher and indicate much more active corrosionongoing. When the alloy is in the active region of the curves (around 0V), then this is where good quality selective dissolution of the betaphase takes place (after an initial cathodic bias).

Atomic force microscopy imaging of Ti-6Al-4V, seen in FIG. 4, shows thatthe alpha phase surface oxide is also modified by the method of thepresent invention and may influence the interaction between the alloyand the biological system. The retained alpha phase surfaces show aporous hydrated oxide surface having beneficial effects on biologicalinteraction along with the nanotopographic pits in the surface.

Example 1

Samples of medical grade Ti-6Al-4V-ELI (Extra-low-interstitial, ASTMF136 “Standard Specification for Wrought Titanium 6AL-4V ELI Alloy forSurgical Implant Applications”) were mechanically polished withincreasing grit emory paper followed by polishing with 1.0, 0.3 and 0.05μm Al₂O₃ particles suspended in water to yield a flat polished surface.These samples were then placed in an electrochemical cell and immersedin a PBS-H₂O₂ solution consisting of 0.154 M phosphate buffered saline(Sigma-Aldrich), and modified with 1 M H₂O₂. The sample was thenelectrochemical held at a voltage of −1V vs Ag/AgCl for 10 min,afterward the potential of the surface was scanned anodically at 1 mV/sup to 1 V vs Ag/Ag/Cl. At the end of this potential scan, the sample wasremoved from the solution, rinsed in DI water and allowed to dry.Afterward the sample was placed in the scanning electron microscope andimaged under secondary electrons. The resultant surface is seen in FIG.5. The beta phase crystals of the microstructure have been selectiveetched away.

Example 2

Samples of Ti-6Al-4V were prepared as in example 1 above. In thisprocess, the sample is first held at a cathodic potential (−1V vsAg/AgCl) for a period of 10 minutes and then immediately scanned up tomore positive potentials at 1 mV/s and then held fixed for periods oftime (typically 1000 s). The potential explored were: −0.5V, −0.1 V, and0.1 V. These last two potentials relate to the active region of thepolarization plots shown in FIG. 2, while −0.5V is still in thesomewhat-cathodic potential region. The solution used to perform thiswas the same as that example 1 (1M H₂O₂ in PBS). After the process wascomplete, the samples were removed from the solution, rinsed in DIwater, dried and imaged in the SEM. The results of Example 2 are seen inFIG. 6. The −0.5 V case (a) did not selectively dissolve the beta phase,while the other two (b) and (c) did.

Example 3

The processed alloy was a commercially pure titanium alloy (ASTM F-36,grade 2). It was prepared and tested as described in example 1, wherethe potential was first held cathodic at −1.0 V and then scannedanodically to +1.0 V at 1 mV/s. Afterward, it was rinsed dried andimaged as above. The results are seen in FIG. 7, and indicate that theCp-Ti surface developed micron-scale and nano-scale pits in the surface.

The method of the present invention may thus be used for the preparationof Ti-alloy surfaces for implantation into biological systems to enhancethe interaction between the body and the implant. This process could beapplied to a wide variety of medical devices where implant-tissueinteractions are important. These include bone implant devices, dentalimplants and potential cardiovascular implants. The resulting effectallows modification of surfaces of titanium alloys to develop micron orsmaller (nano-scale) surface topographic features that may enhance thesesurfaces ability to bond to other materials so it may have applicationsin metal adhesive technology. There are additional advantages to themethod of the present invention in that the beta phase usually containsincreased levels of vanadium, which is feared to diminish or reduce thebiocompatibility of the surface. Selective removal of this vanadium-richphase from the surface of these titanium implants may enhance theoverall biocompatibility of the device and provide faster, stronger ormore robust interfacial adhesion to the biological system. In addition,the gel-like oxide film may have the capability to enhance breakdown ofinflammatory mediators and diminish inflammatory response in the shortterm, and may also enhance the biocompatibility of the surface such asinducing hydroxapatite (HA) coating formation in vivo.

1. A method of preparing a metallic biomedical surface, comprising thesteps of: positioning a three-dimensional, non planar surface comprisinga titanium alloy having an alpha and a beta phase in an electrochemicalcell; immersing said alloy in a non-acidic, ionic aqueous electrolytesolution containing hydrogen peroxide; cathodically biasing said alloyto a negative voltage state for a first predetermined time period; andraising the anodic potential of the alloy for a second predeterminedperiod of time to selectively dissolve the beta phase of the alloy. 2.The method of claim 1, wherein said alloy comprises Ti-6Al-4V.
 3. Themethod of claim 1, wherein said first predetermined period of time isabout ten minutes.
 4. The method of claim 1, wherein the step ofcathodically biasing said alloy to a negative voltage state for a firstpredetermined time period comprises electrochemically holding said alloyat a voltage of −1V.
 5. The method of claim 1, wherein said ionicaqueous electrolyte solution comprises a phosphate buffered salinesolution modified with hydrogen peroxide.
 6. The method of claim 5,wherein said solution comprises hydrogen peroxide in a molarconcentration range of 0.3 to 5.0 M.
 7. The method of claim 6, whereinsaid solution comprises 0.154 M phosphate buffered saline modified with1 M hydrogen peroxide.
 8. A method of preparing a metallic biomedicalsurface, comprising the steps of: positioning a titanium alloy in anelectrochemical cell; immersing said alloy in an ionic aqueouselectrolyte solution containing hydrogen peroxide; cathodically biasingsaid alloy to a negative voltage state for a first predetermined timeperiod by electrochemically holding said alloy at a voltage of −1 V; andraising the anodic potential of the alloy for a second predeterminedperiod of time by anodically scanning said alloy at 1 mV per second to avoltage of 1 V.
 9. A method of preparing a metallic biomedical surface,comprising the steps of: positioning a three-dimensional, non planarsurface comprising a titanium alloy having an alpha and a beta phase inan electrochemical cell; immersing said alloy in a non-acidic, phosphatebuffered solution of saline and hydrogen peroxide; cathodically biasingsaid alloy to voltage state of about −1V for a predetermined timeperiod; and raising the anodic potential of the alloy to a voltage ofabout to selectively dissolve the beta phase of the alloy.
 10. Themethod of claim 9, further comprising the step of preparing the surfaceof said titanium alloy before positioning said titanium alloy in saidelectrochemical cell.
 11. The method of claim 10 wherein the step ofpreparing the surface of said titanium alloy comprises mechanicallypolishing said titanium alloy.
 12. The method of claim 11, whereinmechanically polishing said titanium alloy comprises polishing withaluminum oxide particles suspended in water.
 13. The method of claim 12,wherein the step of preparing the surface of said titanium alloycomprises the steps of heating said titanium alloy into the beta-phaseregion of said titanium alloy and cooling said titanium alloy, therebyforming a Widmanstatten structure.